Group A Streptococcus (GAS) is a major human pathogen that causes a variety of diseases, including relatively mild pharyngitis and skin infection and severe invasive infections such as sepsis and necrotizing fasciitis. Unfortunately, there is no licensed GAS vaccine, and severe invasive infections are difficult to treat with conventional antibiotics. A fundamental understanding of GAS pathogenesis is essential to the development of novel strategies to prevent and treat infections caused by this organism. The goal of this project is to clarify the mechanism for evasion of innate immunity by GAS. Based upon our preliminary studies, we hypothesize that the secreted esterase of GAS (designated SsE) plays a critical role in the inhibition of early neutrophil recruitment by GAS, which then allows the systemic spread of GAS to cause severe disease like sepsis. We further hypothesize that SsE hydrolyzes the platelet-activating factor and acts in tandem with other factor(s) to impede neutrophil responses. We pursue the following specific aims: (1) Determine whether SsE is required for inhibition of early neutrophil recruitment by GAS; (2) Determine whether SsE mediates inhibition of early neutrophil infiltration via hydrolysis of platelet-activating factor; nd (3) Test whether streptolysin S is responsible for the late collapse of neutrophil responses during subcutaneous infection of a sse mutant of a hypervirulent serotype M3 strain. The proposed studies promote two advancements. First, they will increase our understanding of GAS pathogenesis and progression of invasive GAS infections. Second, as a result, they will identify targets for development of a broad, efficacious GAS vaccine and new therapies for prevention and treatment of GAS infections. Overall, this project has the potential to define a novel mechanism for evasion of innate immunity by GAS and to establish a paradigm for bacterial inhibition of neutrophil recruitment and function. PUBLIC HEALTH RELEVANCE: Medical significance: Group A Streptococcus (GAS) is a major cause of acute pharyngitis and severe invasive infections in humans. Unfortunately, no licensed GAS vaccine is available, and severe invasive GAS infections, including necrotizing fasciitis, are difficult to treat with current antibiotics. Investigation of how GAS evades the innte immune system will advance the understanding of GAS pathogenesis and its interaction with the host. These studies have potential to identify targets for developing novel therapy and broad vaccine for treat and prevent GAS infections.